1. Field of the Invention
The present invention relates to a method for treatment or prevention of infections, and particularly opportunistic infections of one or more of Cryptosporidium parvum, Isospora belli, Enterocytzoon bieneusi, Encephalitozoon intestinalis, Mycobacterium tuberculosis, Mycobacterium avium intracellulare, Pneumocystis carinii, and Toxoplasma gondii in persons with compromised or suppressed immune systems, the method comprising administration of a pharmaceutical composition containing as active agent a compound selected fromthe group consisting of a desacetyl-nitazoxanide and nitazoxanide.
2. Description of the Related Art
There is an urgent need for the development of methods for treatment or prevention of a number of parasitic and bacterial infections prevalent in humans and animals, particularly in humans with compromised immune systems (AIDS, cancer patients, elderly, aging). Nitazoxanide, desacetyl-nitazoxanide and combinations thereof may be very useful in treating or preventing many of the most common "opportunistic" bacterial or parasitic infections in person with either competent or compromised immune systems.
Toxoplasma gondii is a protozoan and is among the most prevalent causes of latent infection of the central nervous system throughout the world. Infection occurs primarily via the oral route through ingestion of raw or undercooked meat or contact with cat excrement. Many healthy people are infected with the parasite, but usually the immune system keeps the organism under control. The most frequent symptoms include headache, confusion, fever, and focal neurologic deficits. T. gondii is also the most common opportunistic pathogen of the brain in AIDS patients. At present, toxoplasmosis is becoming an increasing problem not only because of AIDS, but also because of wider use of immunosuppressive drugs (e.g., as administered to organ-transplant patients). Toxoplasmosis is also a threat to the fetus and newborn infant, even in healthy persons without immune suppression.
Toxoplasmosis is usually treated with a combination of pyrimethamine and sulfadiazine (leucovorin must be given with the pyrimethamine). While the drugs are effective, they do not kill cysts of the parasite, so the treatment must be continued as a maintenance dose; often toxicity forces discontinuation of the drug, and relapses result. The statistics are not good, with reported death rates of about 70 percent in immunodeficient patients and median survival of four months.
Cryptosporidiosis is caused by the microscopic protozoan parasite Cryptosporidium parvum. Symptoms include profuse diarrhea, abdominal cramping, urgency, severe dehydration and weight loss. In persons with normal immune functions, the diarrhea caused by C. parvum may be intense and prolonged, but is self-limiting. In AIDS patients, cryptosporidial diarrhea poses a serious health risk, as the disease can be chronic, severe and often life-threatening. It is estimated that 15-20 percent of AIDS patients suffer from this condition. Up to now, there has been no consistently effective or approved therapy for cryptosporidiosis.
The most frequently identified pathogen in AIDS patients is Enterocytozoon bieneusi, a microsporidian parasite, which was found in nearly one-quarter of the patients. Smaller even than Cryptosporidium, it now appears that this tiny parasite, which can only be identified in biopsies of the small intestine or duodenum that are examined by electron microscope, may turn out to be the cause of a large proportion of the many unexplained cases of malabsorption, diarrhea and wasting seen in HIV-ill patients. E. bieneusi lives mainly inside small intestinal cells, but has also been reported as a cause of sinusitis. It causes a specific pattern of damage to mucuous membrane resulting in malabsorption and diarrhea, which both contribute to malnutrition. The dying cells appear to release the organism's tiny spores into the gut. There is no known treatment as yet.
Several other species of microsporidia infect HIV-positive patients, including Encephalitozoon hellem and cuniculi, and a new species designated Septata intestinalis. Encephalitozoon hellem, cuniculi and Septata intestinalis have produced disseminated infections with symptoms mainly in the sinus or eyes. A recent report describes several patients with symptomatic and asymptomatic pulmonary microsporidiosis resulting from E. hellem, and suggests that disseminated microsporidia infections are increasing in significance.
Infection with the parasite Isospora belli is clinically indistinguishable from cryptosporidiosis, but it can usually be treated with trimethoprim-sulfamethoxazole or other sulfa drugs. The organism is larger than Cryptosporidium parvum and can be identified with the same staining techniques. More common in tropical climates, I. belli has been reported in less than 1% of patients in the U.S., although its actual incidence is probably higher. While there have been no controlled trials of sulfa alternatives in treatment of Isospora, there are anecdotal reports of both success and failure with quinacrine, roxythromycin, metronidazole or nitrofurantoin.
Pneumocystis carinii has generally been classified as a protozoan parasite; some studies indicate it may be a fungus, with which it shares certain genetic sequences. P. carinii usually infects the lungs (Pneumocystis Carinii Pneumonia (PCP)), and more rarely infects extrapulmonary sites, including the lymph nodes, bone marrow, spleen, and liver. Symptoms include fever, dry cough, chest tightness, and difficulty breathing. Therapy is reported to be successful in about 40-60% of patients, with problems including drug toxicity particularly in immunocompromised patients. Among the many serious manifestations of human immunodeficiency virus (HIV) infection in children, PCP stands out because of its high incidence, unique age distribution, and frequent mortality. PCP is the most common serious opportunistic infection in children with HIV infection; the incidence of PCP among HIV-infected infants not receiving prophylaxis is estimated to be at least 12% in the first year of life. Many children die shortly alter PCP develops; one survey found that 31% of 300 children with PCP diagnosed in 1991 and 1993 died within 2 months of the PCP diagnosis.
Mycobacterium Avium Complex (MAC) refers to infections by a family of very similar mycobacterial organisms, Mycobacterium avium and M. intracellulare. These bacteria are ubiquitous in soil, food, and water. When MAC occurs in non-immunocompromised people, it usually causes infection in the respiratory tract. In patients with AIDS, MAC is frequently disseminated (disseminated MAC or DMAC). Almost any organ system can be involved, especially those with many mononuclear phagocytes (e.g., the liver, spleen and bone marrow). In a recent study, MAC bacterial was found in 43% of patients who survived for 2 years after an AIDS diagnosis. Signs and symptoms of DMAC are generally nonspecific, such as fever, night sweats, weight loss, weakness, and anorexia. Diarrhea, malabsorption, and abdominal pain may indicate gastrointestinal involvement; enlargement of the liver and spleen is common. No standard therapy has been established for disseminated MAC. Combinations of drugs are usually prescribed and, if successful, require that treatment be continued for life. In a recent open, randomized study, at 6 months, the success rate (defined as alive with decreased fever and negative blood cultures) was 28% for patients in a clarithromycin and clofazimine group and 46% in a triple combination group. A more effective treatment is urgently needed.
HIV-infected people are particularly susceptible to infection by Mycobacterium tuberculosis, and the course of the disease is accelerated. While extrapulmonary tuberculosis is unusual in non-HIV-infected patients, it frequently occurs in HIV-positive people. The lymphatic system is frequently involved. The classic symptoms of tuberculosis (cough, weight loss, fever, night sweats, fatigue) are often present. The CDC has released guidelines for the treatment of TB which address the growing prevalence of multi-drug resistant TB (MDR-TB). Mortality among AIDS patients with MDR-TB is very high (approximately 80%) and the disease progression is extremely rapid.
Accordingly, there is an urgent need for the development of a method of treatment of these infections so prevalent in, and threatening to, humans and animals.